It is our hypothesis that there are genes that are associated with neuropsychiatric and neurodegenerative disorders. It is therefore our specific aim to identify differentially expressed genes by differential display of expressed cDNAs obtained from discrete areas of normal and diseased brains. Our research is focused on the understanding of the pathophysiology of Parkinsons, schizophrenia and bipolar diseases at the molecular level. In Parkinsons disease, total RNA was isolated from microdissected human brain substantia nigra compacta. In schizophrenia, bipolar disease and normal brains the gray matter of the frontal and cingulate cortices was extracted for total RNA. Differentially expressed genes were isolated, reamplified and sequenced. The sequences obtained were compared with GenBank and EST databases. In the three diseases studied, a number of known and unknown cDNAs were found to be differentially expressed. In Parkinsons disease the genes that were down-regulated were complex I and complex IV, neurofilament protein, dynein, hevin, and 15 unknown genes. The genes that were up-regulated were GEF (guanine nucleotide exchange factor), catalase, flotillin-1 and three unknown genes. We have focused our attention on flotillin-1, a novel gene which is implicated in the formation of caveolae, the vesicular organelles. We were successful in demonstrating the presence of the flotillin-1 mRNA in human brain by in situ hybridization histochemistry. In schizophrenia, a number of known and unknown cDNAs were found to be differentially expressed. Among the unknown cDNAs, one was found to be down-regulated in the bipolar brain, and four were found to be down-regulated in both the bipolar and the schizophrenic brains. Among the known candidate genes, the expression of Wnt-13 was up-regulated in the cortices of the schizophrenic brain. Several lines of evidence indicate that the wingless/Wnt pathway participates in a complex behavioral phenomenon and that the molecules involved in this pathway are implicated as candidate genes for neuropsychiatric disorders. Recently, the expression of Wnt-1 has been shown to be increased in the schizophrenic brains. Wnt-1 has been shown to play an important role in a variety of developmental processes including midbrain and hindbrain development through knock-out mouse studies. Since Wnt-13 shares common expression features with Wnt-1, it is possible that the Wnt pathway is altered in the schizophrenic brain. In bipolar disease, five genes were found to be down-regulated and three were up-regulated. Four genes were down-regulated in both the bipolar and schizophrenic brains. One down-regulated transcript maps to chromosome 12q24 which has recently been reported to be in the linkage region for bipolar disease. We have the complete genomic structure of this transcript. Future studies will scan for mutations of this gene. - PARKINSON'S DISEASE, NEURODEGENERATIVE DISEASE, DIFFERENTIAL DISPLAY, SCHIZOPHRENIA, BIPOLAR, FLOTILLIN, WNT-13